Department of Clinical Tumor Biology, University Hospital, University of Tübingen, Tübingen, Germany.
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Tübingen, Germany.
Neuroendocrinology. 2019;109(4):346-361. doi: 10.1159/000500159. Epub 2019 Jun 13.
Metastatic neuroendocrine cancer still constitutes a palliative situation, lacking promising treatment options. Oncolytic virotherapy, a novel type of virus-based immunotherapy, lyses tumor cells using genetically engineered viruses thereby activating the immune system to induce an optimized antitumor response which could bring down tumor masses to a stage of minimal residual tumor disease. The oncolytic vector talimogene laherparepvec (T-VEC, herpes simplex virus [HSV] type 1) has already shown excellent safety profiles in clinical studies and has become the first ever FDA/EMA-approved oncolytic virus (OV). This work presents a first preclinical assessment of this state-of-the-art OV, using a panel of human neuroendocrine tumor/neuroendocrine carcinoma (NET/NEC) cell lines. Cytotoxicity, transgene expression, and viral replication patterns were studied. Furthermore, the antiproliferative activity was compared to the one of mTOR inhibitor Everolimus and also interactions between the OV and Everolimus were evaluated. Moreover, virostatic effects of ganciclovir (GCV) on replication of T-VEC were assessed and electron microscopic pictures were taken to comprehend viral envelopment and details of the replication cycle of T-VEC in human neuroendocrine cancer. It could be shown that T-VEC infects, replicates in, and lyses human NET/NEC cells exhibiting high oncolytic efficiencies already at quite low virus concentrations. Interestingly, Everolimus was not found to have any relevant impact on rates of viral replication, but no additive effects could be proved using a combinatorial therapy regimen. On the other hand, GCV was shown to be able to limit replication of T-VEC, thus establishing an important safety feature for future treatments of NET/NEC patients. Taken together, T-VEC opens up a promising novel treatment option for NET/NEC patients, warranting its further preclinical and clinical development.
转移性神经内分泌癌仍然是一种姑息性情况，缺乏有前途的治疗选择。溶瘤病毒治疗是一种新型的基于病毒的免疫疗法，使用基因工程病毒裂解肿瘤细胞，从而激活免疫系统，诱导优化的抗肿瘤反应，使肿瘤缩小到微小残留肿瘤疾病阶段。溶瘤病毒载体替莫唑胺拉滨（talimogene laherparepvec，T-VEC，单纯疱疹病毒[HSV] 1 型）在临床研究中已显示出优异的安全性，并已成为首个获得 FDA/EMA 批准的溶瘤病毒（OV）。本研究首次对这种最先进的 OV 进行了临床前评估，使用了一系列人神经内分泌肿瘤/神经内分泌癌（NET/NEC）细胞系。研究了细胞毒性、转基因表达和病毒复制模式。此外，还比较了该 OV 的抗增殖活性与 mTOR 抑制剂依维莫司的活性，并评估了 OV 和依维莫司之间的相互作用。此外，评估了更昔洛韦（GCV）对 T-VEC 复制的病毒静态作用，并拍摄电子显微镜照片，以了解 T-VEC 在人神经内分泌癌中的包膜和复制周期的细节。结果表明，T-VEC 感染、复制并裂解人 NET/NEC 细胞，即使在相当低的病毒浓度下，也表现出很高的溶瘤效率。有趣的是，依维莫司对病毒复制率没有任何显著影响，但在联合治疗方案中没有证明有任何相加作用。另一方面，GCV 能够限制 T-VEC 的复制，从而为未来 NET/NEC 患者的治疗建立了一个重要的安全特征。总之，T-VEC 为 NET/NEC 患者提供了一种有前途的新的治疗选择，值得进一步进行临床前和临床开发。
